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49-441: The antidepressant medication Trazodone was developed in the 1960s by scientists at Angelini. Since 2000, Angelini has been the producer of Amuchina , the sanitizing solution invented by Oronzio De Nora . In a 2018, evaluation of firms' reputation issued by Reputation Institute, Angelini ranked 66th in general and second among life sciences companies. In 2020, Angelini took over ownership of Thermacare after Pfizer spun off

98-854: A 5-HT 2A receptor antagonist to mediate its therapeutic benefits against anxiety and depression . Its inhibitory effects on serotonin reuptake and 5-HT 2C receptors are comparatively weak. In relation to these properties, trazodone does not have similar properties to selective serotonin reuptake inhibitors (SSRIs) and is not particularly associated with increased appetite and weight gain – unlike other 5-HT 2C antagonists like mirtazapine . Moderate 5-HT 1A partial agonism may contribute to trazodone's antidepressant and anxiolytic actions to some extent as well. The combined actions of 5-HT 2A and 5HT 2C receptor antagonism with serotonin reuptake inhibition only occur at moderate to high doses of trazodone. Doses of trazodone lower than those effective for antidepressant action are frequently used for

147-540: A consequence of α 1 -adrenergic receptor blockade. The unmasking of bipolar disorder may occur with trazodone and other antidepressants. Precautions for trazodone include known hypersensitivity to trazodone and under 18 years and combined with other antidepressant medications, it may increase the possibility of suicidal thoughts or actions. While trazodone is not a true member of the SSRI class of antidepressants, it does still share many properties of SSRIs, especially

196-480: A few of the other second-generation antidepressants in overdose situations, especially when it is the only agent taken. Fatalities are rare, and uneventful recoveries have been reported after ingestion of doses as high as 6,000–9,200   mg. In one report, 9 of 294 cases of overdose were fatal, and all nine patients had also taken other central nervous system (CNS) depressants. When trazodone overdoses occur, clinicians should carefully monitor for low blood pressure ,

245-457: A metabolite hydroxylated at the para position of the meta -chlorophenyl ring (via CYP2D6), oxotriazolepyridinepropionic acid (TPA) and mCPP (both via N -dealkylation of the piperazinyl nitrogen mediated by CYP3A4), and a metabolite formed by N-oxidation of the piperazinyl nitrogen. CYP1A2, CYP2D6, and CYP3A4 genotypes all do not seem to predict concentrations of trazodone or mCPP. In any case, there are large interindividual variations in

294-442: A non-selective serotonin receptor modulator and serotonin releasing agent , is an active metabolite of trazodone and has been suggested to possibly play a role in its therapeutic benefits. However, research has not supported this hypothesis and mCPP might actually antagonize the efficacy of trazodone as well as produce additional side effects. Trazodone is well- absorbed after oral administration . Its bioavailability

343-438: A potentially serious toxic effect. In a report of a fatal trazodone overdose, torsades de pointes and complete atrioventricular block developed, along with subsequent multiple organ failure, with a trazodone plasma concentration of 25.4   mg/L on admission. Trazodone is metabolized by several liver enzymes , including CYP3A4 , CYP2D6 , and CYP1A2 . Its active metabolite meta -chlorophenylpiperazine (mCPP)

392-419: A side effect of trazodone, orthostatic hypotension , which may cause dizziness and increase the risk of falling, can have devastating consequences for elderly patients. Therefore, this side effect, along with sedation, often makes trazodone less acceptable for this population compared to newer compounds that share its lack of anticholinergic activity (but not the rest of its side effect profile). Still, trazodone

441-436: A sleep aid are currently lacking. Trazodone is used at low doses in the range of 50 to 150   mg/day for insomnia. Higher doses of 200 to 600   mg/day have also been studied. The American Academy of Sleep Medicine 's 2017 clinical practice guidelines recommended against the use of trazodone in the treatment of insomnia due to inadequate evidence and due to harms potentially outweighing benefits. Trazodone

490-610: A so-called " trip killer " by recreational psychedelic users. It was recommended on the social media website Reddit for such purposes 77   times by 2024 with a suggested dose range of 50 to 150   mg. Trazodone was one of the most commonly recommended drugs for such purposes, exceeded only by alprazolam , benzodiazepines generally, and quetiapine . Trazodone is a mixed agonist and antagonist of various serotonin receptors , antagonist of adrenergic receptors , weak histamine H 1 receptor antagonist, and weak serotonin reuptake inhibitor . More specifically, it

539-575: A strong CYP3A4 and CYP2D6 inhibitor and moderate CYP1A2 inducer, increased trazodone peak levels by 1.4-fold, trazodone area-under-the-curve levels by 2.4-fold, and decreased trazodone clearance by 50%. This was associated with adverse effects such as nausea , hypotension , and syncope . Another study found that the strong CYP3A4 inducer carbamazepine reduced concentrations of trazodone by 60 to 74%. The strong CYP2D6 inhibitor thioridazine has been reported to increase trazodone levels by 1.4-fold and concentrations of mCPP by 1.5-fold. Fluoxetine,

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588-566: A strong inhibitor of CYP2D6 and a weak or moderate inhibitor of CYP3A4, has been reported to increase levels of trazodone by 1.3- to 1.7-fold and of mCPP by 3.0- to 3.4-fold. Conversely, CYP2D6 genotype has not been found to predict trazodone or mCPP concentrations with trazodone therapy, although CYP2D6 genotype did correlate with side effects like dizziness and prolonged corrected QT interval . Smokers have lower levels of trazodone and higher ratios of mCPP to trazodone. Trazodone levels were 30% lower in smokers and mCPP to trazodone ratio

637-441: Is priapism , likely due to its antagonism at α-adrenergic receptors. More than 200 cases have been reported, and the manufacturer estimated that the incidence of any abnormal erectile function is about one in 6,000 male patients treated with trazodone. The risk for this side effect appears to be greatest during the first month of treatment at low dosages (i.e. <150   mg/day). Early recognition of any abnormal erectile function

686-461: Is 65 to 80%. Peak blood levels of trazodone occur 1 to 2   hours after ingestion and peak levels of the metabolite mCPP occur after 2 to 4   hours. Absorption is somewhat delayed and enhanced by food. Trazodone is not sequestered into any tissue . The medication is 89 to 95% protein-bound . The volume of distribution of trazodone is 0.8 to 1.5   L/kg. Trazodone is highly lipophilic . The metabolic pathways involved in

735-589: Is a stub . You can help Misplaced Pages by expanding it . Trazodone Trazodone , sold under many brand names, is an antidepressant medication, used to treat major depressive disorder , anxiety disorders , and insomnia . It is a phenylpiperazine compound of the serotonin antagonist and reuptake inhibitor (SARI) class. The medication is taken orally . Common side effects include dry mouth , feeling faint, vomiting, and headache. More serious side effects may include suicide , mania , irregular heart rate , and pathologically prolonged erections . It

784-481: Is a 5-HT 1A receptor partial agonist similarly to buspirone and tandospirone but with comparatively greater intrinsic activity . A range of weak affinities (K i ) have been reported for trazodone at the human histamine H 1 receptor , including 220   nM, 350   nM, 500   nM, and 1,100   nM. Trazodone has a minor active metabolite known as meta -chlorophenylpiperazine (mCPP), and this metabolite may contribute to some degree to

833-428: Is an antagonist of 5-HT 2A and 5-HT 2B receptors , a partial agonist of the 5-HT 1A receptor , and an antagonist of the α 1 - and α 2 -adrenergic receptors . It is also a ligand of the 5-HT 2C receptor with lower affinity than for the 5-HT 2A receptor. However, it is unknown whether trazodone acts as a full agonist , partial agonist, or antagonist of the 5-HT 2C receptor. Trazodone

882-533: Is associated with increased risk of falls in older adults. It has also been associated with increased risk of hip fractures in older adults. Sufficient data in humans are lacking. Use should be justified by the severity of the condition to be treated. There are reported cases of high doses of trazodone precipitating serotonin syndrome . There are also reports of patients taking multiple SSRIs with trazodone and precipitating serotonin syndrome. Trazodone appears to be relatively safer than TCAs , MAOIs , and

931-612: Is especially useful in situations in which antimuscarinic effects are particularly problematic (e.g., in patients with benign prostatic hyperplasia , closed-angle glaucoma, or severe constipation). Trazodone's propensity to cause sedation is a dual-edged sword. For many patients, the relief from agitation, anxiety, and insomnia can be rapid; for other patients, including those individuals with considerable psychomotor retardation and feelings of low energy, therapeutic doses of trazodone may not be tolerable because of sedation. Trazodone elicits orthostatic hypotension in some people, probably as

980-442: Is important, including prolonged or inappropriate erections, and should prompt discontinuation of trazodone treatment. Spontaneous orgasms have also been reported with trazodone in men. Clinical reports have described trazodone-associated psychosexual side effects in women as well, including increased libido , priapism of the clitoris, and spontaneous orgasms . Rare cases of liver toxicity have been observed, possibly due to

1029-1629: Is known to be formed by CYP3A4 and metabolized by CYP2D6. Inhibition or induction of the aforementioned enzymes by various other substances may alter the metabolism of trazodone and/or mCPP, leading to increased and/or decreased blood concentrations. The enzymes in question are known to be inhibited and induced by many medications, herbs, and foods, and as such, trazodone may interact with these substances. Potent CYP3A4 inhibitors such as clarithromycin , erythromycin , fluvoxamine , grapefruit juice , ketoconazole , and ritonavir may lead to increased concentrations of trazodone and decreased concentrations of mCPP, while CYP3A4 inducers like carbamazepine , enzalutamide , phenytoin , phenobarbital , and St. John's wort may result in decreased trazodone concentrations and increased mCPP concentrations. CYP2D6 inhibitors may result in increased concentrations of both trazodone and mCPP, while CYP2D6 inducers may decrease their concentrations. Examples of potent CYP2D6 inhibitors include bupropion , cannabidiol , duloxetine , fluoxetine , paroxetine , quinidine , and ritonavir, while CYP2D6 inducers include dexamethasone , glutethimide , and haloperidol . CYP1A2 inhibitors may increase trazodone concentrations, while CYP1A2 inducers may decrease trazodone concentrations. Examples of potent CYP1A2 inhibitors include ethinylestradiol (found in hormonal birth control ), fluoroquinolones (e.g., ciprofloxacin ), fluvoxamine, and St. John's wort , while potent CYP1A2 inducers include phenytoin, rifampin , ritonavir, and tobacco . A study found that ritonavir,

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1078-488: Is less studied in blocking the effects of serotonergic psychedelics than other serotonin 5-HT 2A receptor antagonists like ketanserin and risperidone, but was reported to reduce the effects of LSD in one published case report . Specifically, a woman on trazodone 200   mg/day who received a "moderate" dose of LSD was reported to have had reduced LSD-related hallucinogenic and physiological effects. Additionally, trazodone has been used and discussed extensively online as

1127-437: Is often helpful for geriatric patients with depression who have severe agitation and insomnia. Trazodone is usually used at a dosage of 150 to 300   mg/day for the treatment of depression. Lower doses have also been used to augment other antidepressants or when initiating therapy. Higher doses, up to 600   mg/day, have been used in more severe cases of depression (in hospitalized patients, for example). Trazodone

1176-444: Is often necessary for patients with a major depressive episode. Not only can a hypnotic potentially relieve the insomnia itself, but treating insomnia in patients with major depression may also increase remission rates due to improvement of other symptoms such as loss of energy and depressed mood. Thus, the ability of low doses of trazodone to improve sleep in depressed patients may be an important mechanism whereby trazodone can augment

1225-441: Is often used in the treatment of anxiety disorders — such as generalized anxiety disorder and panic disorder — as well as in post-traumatic stress disorder (PTSD) and obsessive–compulsive disorder (OCD). Trazodone is often used as an alternative to benzodiazepines in the treatment of anxiety disorders. However, use of trazodone in anxiety disorders is off-label and evidence of its effectiveness for these indications

1274-470: Is provided as the hydrochloride salt and is available in the form of 50   mg, 100   mg, 150   mg, and 300   mg oral tablets . In Italy, it is also available as an oral solution (Trittico 60 mg/mL) with a dosing pipette marked at 25 mg and 50 mg. An extended-release oral tablet formulation at doses of 150   mg and 300   mg is also available. Because of its lack of anticholinergic side effects, trazodone

1323-1099: Is thus recommended. Since trazodone may impair the mental and/or physical abilities required for performance of potentially hazardous tasks, such as operating an automobile or machinery, the patient should be cautioned not to engage in such activities while impaired. Compared to the reversible MAOI antidepressant drug moclobemide , more impairment of vigilance occurs with trazodone. Trazodone has been found to impair driving ability. Case reports have noted cardiac arrhythmias emerging in relation to trazodone treatment, both in patients with pre-existing mitral valve prolapse and in patients with negative personal and family histories of cardiac disease. QT prolongation has been reported with trazodone therapy. Arrhythmia identified include isolated PVCs , ventricular couplets, and in two patients short episodes (three to four beats) of ventricular tachycardia . Several post-marketing reports have been made of arrhythmia in trazodone-treated patients who have pre-existing cardiac disease and in some patients who did not have pre-existing cardiac disease. Until

1372-581: Is unclear if use during pregnancy or breastfeeding is safe. Trazodone also has sedating effects. Trazodone was approved for medical use in the United States in 1981. It is available as a generic medication . In 2022, it was the eighteenth most commonly prescribed medication in the United States, with more than 27   million prescriptions. The primary use of trazodone is the treatment of unipolar major depression with or without anxiety . Data from open and double-blind trials suggest that

1421-558: Is usually administered multiple times per day, but once-daily administration may be similarly effective. Low-dose trazodone is used off-label in the treatment of insomnia and is considered to be effective and safe for this indication. It may also be used to treat antidepressant -related insomnia. Trazodone was the second-most prescribed agent for insomnia in the early 2000s even though most studies of trazodone for treatment of sleep disturbances have been in depressed individuals. Systematic reviews and meta-analyses published in

1470-481: Is variable and limited. Benefits for OCD appear to be mild. Trazodone has been used to treat sleep disturbances and nightmares in PTSD. Trazodone is often used in combination with other antidepressants such as selective serotonin reuptake inhibitors in order to augment their antidepressant and anxiolytic effects and to reduce side effects such as sexual dysfunction , anxiety, and insomnia. Trazodone

1519-574: The transdermal analgesic patch after its merger with GlaxoSmithKline 's consumer healthcare division. In January 2021, the Swiss biotech company Arvelle Therapeutics was acquired for $ 960 million. In 2022 the Angelini has been rebranded as "Angelini Industries". The new brand has been adopted by Angelini Pharma, Angelini Technologies, Angelini Wines & Estates, Angelini Beauty and Angelini Ventures. This Italian corporation or company article

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1568-400: The 5-HT 2A receptor relative to the 5-HT 2C receptor. In addition, at higher doses, trazodone acts as a dopamine D 2 receptor antagonist in animals. As a result of the preceding actions, trazodone may inhibit striatal dopaminergic neurotransmission. This may underlie exacerbation of parkinsonism seen in marmosets and in human case reports . Trazodone may act predominantly as

1617-571: The 5-HT 2A receptor, serotonin 5-HT 2A receptor antagonists can block the hallucinogenic effects of serotonergic psychedelics. Serotonin 5-HT 2A receptor antagonists like ketanserin and risperidone have been found to fully block or dose-dependently reduce the subjective effects of LSD and psilocybin in clinical studies . Trazodone is a potent serotonin 5-HT 2A receptor antagonist and may have similar effects. Studies have estimated that trazodone occupies 90 to 97% of 5-HT 2A receptors at doses of 50 to 200   mg/day. Trazodone

1666-823: The SERT and 5-HT 2A receptors by trazodone. Trazodone shows antidepressant - and anxiolytic -like effects in animals. However, it shows differences from certain other antidepressants, like the tricyclic antidepressants , in animals. For example, it does not reverse the behavioral effects of the monoamine depleting agent reserpine and does not potentiate the effects of amphetamine or levodopa . Similarly to antipsychotics , trazodone reduces spontaneous motor activity , spontaneous and elicited aggressive behavior , and exploratory behavior , among other effects. In addition, trazodone diminishes amphetamine -induced locomotor hyperactivity , although it does not inhibit apomorphine - or amphetamine -induced stereotypy . On

1715-555: The antidepressant efficacy of trazodone is comparable to that of amitriptyline , doxepin , and mianserin . Furthermore, trazodone has shown anxiolytic properties, low cardiotoxicity , and relatively mild side effects. Because trazodone has minimal anticholinergic activity, it was especially welcomed as a treatment for geriatric patients with depression when it first became available. Three double-blind studies reported trazodone had antidepressant efficacy similar to that of other antidepressants in geriatric patients. Unfortunately,

1764-481: The basis of its common label as an antidepressant of the serotonin antagonist and reuptake inhibitor (SARI) type. Studies have estimated occupancy of target sites by trazodone based on trazodone concentrations in blood and brain and on the affinities of trazodone for the human targets in question. Roughly half of brain 5-HT 2A receptors are blocked by 1   mg of trazodone and essentially all 5-HT 2A receptors are saturated at 10   mg of trazodone, but

1813-475: The clinically effective hypnotic doses of trazodone are in the 25–100   mg range. The occupancy of the serotonin transporter (SERT) by trazodone is estimated to be 86% at 100   mg/day and 90% at 150   mg/day. Trazodone may almost completely occupy the 5-HT 2A and 5-HT 2C receptors at doses of 100 to 150   mg/day. Significant occupancy of a number of other sites may also occur. However, another study estimated much lower occupancy of

1862-409: The effective treatment of insomnia. Low doses exploit trazodone's potent actions as a 5-HT 2A receptor antagonist, and its properties as an antagonist of H 1 and α 1 -adrenergic receptors, but do not adequately exploit its SERT or 5-HT 2C inhibition properties, which are weaker. Since insomnia is one of the most frequent residual symptoms of depression after treatment with an SSRI, a hypnotic

1911-417: The efficacy of other antidepressants. Trazodone's potent α 1 -adrenergic blockade may cause some side effects like orthostatic hypotension and sedation . Conversely, along with 5-HT 2A and H 1 receptor antagonism, it may contribute to its efficacy as a hypnotic . Trazodone lacks any affinity for the muscarinic acetylcholine receptors , so does not produce anticholinergic side effects. mCPP,

1960-415: The formation of reactive metabolites. Elevated prolactin concentrations have been observed in people taking trazodone. They appear to be increased by around 1.5- to 2-fold. Studies on trazodone and cognitive function are mixed, with some finding improvement, others finding no change, and some finding impairment. Trazodone does not seem to worsen periodic limb movements during sleep. Trazodone

2009-692: The late 2010s, including a Cochrane review , found low-dose trazodone to be an effective medication for short-term treatment of insomnia in both depressed and euthymic people. Trazodone slightly improves subjective sleep quality ( SMD Tooltip standardized mean difference = –0.34 to –0.41) and reduces the number of nighttime awakenings ( MD = –0.31, SMD = –0.51), on average. Conversely, it does not appear to affect sleep onset , total sleep time , time awake after sleep onset , or sleep efficiency . It appears to increase deep sleep —in contrast to certain other hypnotics . The quality of evidence of trazodone for short-term treatment of insomnia

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2058-408: The metabolism are not well-characterized. In any case, the cytochrome P450 enzymes CYP3A4 , CYP2D6 , and CYP1A2 may all be involved to varying extents. Trazodone is known to be extensively metabolized by the liver via hydroxylation , N -oxidation , and N -dealkylation . Several metabolites of trazodone have been identified, including a dihydrodiol metabolite (via hydroxylation),

2107-591: The other hand, cases of excessive sedation and serotonin syndrome have been reported with combination of trazodone and fluoxetine or paroxetine. This may be due to combined potentiation of the serotonin system. On the other hand, it may be related to inhibition of cytochrome P450 enzymes by fluoxetine and paroxetine and consequent increased trazodone and mCPP levels. Serotonergic psychedelics like lysergic acid diethylamide (LSD) and psilocybin are thought to mediate their halucinogenic effects by activating serotonin 5-HT 2A receptors . By displacing them from

2156-474: The other hand, unlike antipsychotics, trazodone does not produce catalepsy , although it can do so at sufficiently high doses. Activation of the serotonin 5-HT 2A receptor enhances striatal dopaminergic neurotransmission, while stimulation of the serotonin 5-HT 2C receptor inhibits striatal dopaminergic neurotransmission. Trazodone is both a serotonin 5-HT 2A and 5-HT 2C receptor antagonist, but has about 15-fold greater potency as an antagonist of

2205-734: The pharmacological properties of trazodone. In contrast to trazodone, mCPP is an agonist of various serotonin receptors. It has relatively low affinity for α 1 -adrenergic receptors unlike trazodone, but does high affinity for α 2 -adrenergic receptors and weak affinity for the H 1 receptor. In addition to direct interactions with serotonin receptors, mCPP is a serotonin releasing agent similarly to agents like fenfluramine and MDMA . In contrast to these serotonin releasing agents however, mCPP does not appear to cause long-term serotonin depletion (a property thought to be related to serotonergic neurotoxicity ). Trazodone's 5-HT 2A receptor antagonism and weak serotonin reuptake inhibition form

2254-400: The possibility of discontinuation syndrome if the medication is stopped too quickly. Care must, therefore, be taken when coming off the medication, usually by a gradual process of tapering down the dose over a period of time. Antidepressants may increase the risk of suicidal thoughts and behaviors in children and young adults. Close monitoring for emergence of suicidal thoughts and behaviors

2303-507: The results of prospective studies are available, patients with pre-existing cardiac disease should be closely monitored, particularly for cardiac arrhythmias. Trazodone is not recommended for use during the initial recovery phase of myocardial infarction. Concomitant administration of drugs that prolong the QT interval or that are inhibitors of CYP3A4 may increase the risk of cardiac arrhythmia. A relatively rare side effect associated with trazodone

2352-509: Was 1.3-fold higher in smokers, whereas mCPP concentrations were not different between smokers and non-smokers. Smoking is known to induce CYP1A2, and this may be involved in these findings. Combination of trazodone with selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), or monoamine oxidase inhibitors (MAOIs) has a theoretical risk of serotonin syndrome . However, trazodone has been studied in combination with SSRIs and seemed to be safe in this context. On

2401-411: Was rated as low to moderate. There is no evidence available at present to inform long-term use of trazodone in the treatment of insomnia. The benefits of trazodone for insomnia must be weighed against potential adverse effects , such as morning grogginess , daytime sleepiness , cognitive and motor impairment , and postural hypotension , among others. Quality safety data on use of trazodone as

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